tbuckley/cabot-search huggingface dataset:
Association Between Implementation of a Geriatric Trauma Clinical Pathway and Changes in Rates of Delirium in Older Adults With Traumatic Injury
Authors: Caroline Park, Ankur Bharija, Matthew Mesias, Ann Mitchell, Purnima Krishna, Nannette Storr-Street, Alyssa Brown, Marina Martin, Amy C. Lu, Kristan L. Staudenmayer
Journal: JAMA Surgery (2022)

Older adults (age ≥65 years) are at risk for high rates of delirium and poor outcomes; however, how to improve outcomes is still being explored.To assess whether implementation of a geriatric trauma clinical pathway was associated with reduced rates of delirium in older adults with traumatic injury.A retrospective case-control study of electronic health records of patients aged 65 years or older with traumatic injury from 2018 to 2020 was conducted at a single level I trauma center. Eligible patients were age 65 years or older admitted to the trauma service and who did not undergo an operation.The implementation of a clinical pathway based on geriatric best practices, which included order sets, guidelines, automated consultations, and escalation pathways executed by a multidisciplinary team.The primary outcome was delirium. The secondary outcome was hospital length of stay. Process measures for pathway compliance were also assessed.Of the 859 eligible patients, 712 patients were included in the analysis (442 [62.1%] in the baseline group; 270 [37.9%] in the postimplementation group; mean [SD] age: 81.4 [9.1] years; 394 [55.3%] were female). The mechanism of injury was not different between groups, with 247 in the baseline group (55.9%) and 162 in the postimplementation group (60.0%) (P = .43) experiencing a fall. Injuries were minor or moderate in both groups (261 in baseline group [59.0%] and 168 in postimplementation group [62.2%]; P = .87). The adjusted odds ratio for delirium in the postimplementation cohort was 0.54 (95% CI, 0.37-0.80; P < .001). Goals of care documentation improved significantly in the postimplementation cohort vs the baseline cohort with regard to documented goals of care notes (53.7% in the postimplementation cohort [145 of 270] vs 16.7% in the baseline cohort [74 of 442]; P < .001) and a shortened time to discussion from presenting to the emergency department (36 hours in the postimplementation cohort vs 50 hours in the baseline cohort; P = .03).In this study, implementation of a multidisciplinary clinical pathway for injured older adults at a single level I trauma center was associated with improved care and clinical outcomes. Interventions such as these may have utility in this vulnerable population, and findings should be confirmed across multiple centers.
Abstract 5200: The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI)
Authors: Hyeonseon Kim, Yeun Ho Lee, Chiwoo Song, Leeseul Kim, Min Jeong Kim, Horyun Choi, Jinah Kim, Young Kwang Chae
Journal: Cancer Research (2022)

Abstract Background: HPD is an unexpected rapid acceleration of tumor growth reported for patients treated with ICI. The definition of HPD is not fully established and risk factors are uncertain. Our aim in this study was to find the incidence of HPD as well as its significant clinical and genetic risk factors. Method: A total of 203 patients with NSCLC who received ICI at Northwestern Memorial Hospital during 2008-2020 were included. Tumor growth kinetics (TGK) on immunotherapy and TGK pre-immunotherapy were collected and TGK ratio (TGKR) was calculated. HPD was defined as TGKR≥2. Result: HPD was observed in 16% (n=33) of patients. HPD was significantly associated with high ECOG (3-4 vs 1-2) [OR = 4.52, 95% CI = 1.31 to 16.29, P = 0.01], presence of bone metastasis [OR = 2.51, 95% CI = 1.10 to 5.28, P = 0.01], neutrophils/lymphocyte ratio(NLR) ≥5 [OR = 2.68, 95% CI = 1.24 to 5.81 P = 0.01], thrombocytosis (platelet count &amp;gt;450k) [OR = 5.31, 95% CI = 2.07 to 14.70, P=0.0003], and treatment with PD-L1 inhibitor vs PD-1 inhibitor [OR = 2.14, 95% CI= 0.97 to 4.68, P= 0.068]. HPD was inversely associated with positive PD-L1 expression [OR = 0.34, 95% CI = 0.13 to 0.86, P = 0.01], ICI combined with chemotherapy vs ICI monotherapy [OR = 0.24, 95% CI = 0.055 to 0.97, P=0.04], and positive TTF-1 expression [OR = 0.46, 95% CI = 0.21 to 1.02, P=0.057]. HPD was not associated with histology of NSCLC (adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and large cell neuroendocrine carcinoma), age(&amp;lt;70, ≥70), sex, smoking history, number of metastatic lesions (&amp;lt;3, ≥3), brain metastasis, liver metastasis, brain metastasis before treatment initiation, EGFR mutation, TP53 mutation, BRAF mutation, and TNM staging. Conclusion: The incidence of HPD in NSCLC treated with ICI was consistent with current literature. High NLR and platelet count are suggestive of an immunosuppressive environment that could contribute to the rapid growth of tumors. To our knowledge, this is the first study to report an inverse correlation of PD-L1 expression and TTF-1 expression with HPD. The strength of our study lies in a large number of patients. Further studies on validating risk factors of HPD and exploring their associated mechanisms are warranted. Citation Format: Hyeonseon Kim, Yeun Ho Lee, Chiwoo Song, Leeseul Kim, Min Jeong Kim, Horyun Choi, Jinah Kim, Young Kwang Chae. The incidence and risk factors of hyperprogressive disease(HPD) in non-small cell lung cancer(NSCLC) treated with immune checkpoint inhibitors(ICI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5200.
Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification
Authors: Robert L. Hollis, Alison M. Meynert, Caroline O. Michie, Tzyvia Rye, Michael Churchman, Amelia Hallas-Potts, Ian Croy, W. Glenn McCluggage, Alistair R.W. Williams, Clare Bartos, Yasushi Iida, Aikou Okamoto, Brian Dougherty, J. Carl Barrett, Ruth March, Athena Matakidou, Patricia Roxburgh, Colin A. Semple, D. Paul Harkin, Richard Kennedy, C. Simon Herrington, Charlie Gourley
Journal: Clinical Cancer Research (2022)

High-grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence that accumulates chemoresistance, leading to treatment failure. Genomic and transcriptomic features have been associated with differential outcome and treatment response. However, the relationship between events at the gene sequence, copy number, and gene-expression levels remains poorly defined.We perform multiomic characterization of a large HGSOC cohort (n = 362) with detailed clinical annotation to interrogate the relationship between patient subgroups defined by specific molecular events.BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival [multivariable hazard ratios (HR) 0.40 and 0.51] and significantly higher first- and second-line chemotherapy response rate. CCNE1-gained (CCNE1g) cases demonstrated underrepresentation of FIGO stage IV cases, with shorter survival but no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and Tothill-derived subtypes. IMR/C2 cases displayed higher BRCA1/2m frequency (25.5%, 32.5%) and significantly greater immune cell infiltration, whereas PRO/C5 cases had the highest CCNE1g rate (23.9%, 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all transcriptomic subtypes (HR range, 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations; RB loss was further associated with favorable survival within HRR-aberrant cases (multivariable HR, 0.50).These data paint a high-resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.
Abstract 842: ADAR and DDX54 promote genomic stability in breast cancer cells
Authors: Sua Ryu, Kyle A. Cottrell, Luisángely Soto-Torres, Angela Schabb, Jason D. Weber
Journal: Cancer Research (2022)

Abstract Adenosine deaminase acting on RNA (ADAR) is an RNA-editing enzyme that binds dsRNA and converts adenosine to inosine. ADAR promotes cell survival and proliferation in multiple types of tumors, including breast cancer. However, the mechanism of ADAR-driven oncogenicity is not fully established. We focused on ADAR p110, the constitutively expressed and nuclear-localized isoform, and its role in managing genotoxic stress in cancer. ADAR p110 is involved in resolving R-loops, the DNA-RNA hybrids produced during transcription, and DNA damage response (DDR). We sought to elucidate the mechanism of ADAR-associated R-loop resolution and DDR that can be targeted in breast cancer. To identify ADAR-interacting proteins, proximity labeling was performed using ADAR p110 fused to ascorbate peroxidase (APEX2), followed by mass spectrometry. Among the positively enriched hits, known ADAR-interacting proteins associated with R-loop and DDR were validated by immunoprecipitation and immunofluorescence. DEAD-box helicase DDX54 was among the nine RNA helicases interacting with ADAR. DDX54 and ADAR showed an additive effect on preventing γH2AX signal. Additionally, knockdown (KD) of DDX54 increased ADAR expression, whereas ADAR KD did not affect DDX54 expression. These results suggest that DDX54 coordinates with ADAR to prevent genotoxic stress in breast cancer cells. As DDX54 and ADAR are both associated with R-loop resolution and DDR, we hypothesize that DDX54 and ADAR suppress R-loop accumulation and/or other types of genotoxic stress. This may be through independent pathways despite the physical interaction between ADAR and DDX54. Citation Format: Sua Ryu, Kyle A. Cottrell, Luisángely Soto-Torres, Angela Schabb, Jason D. Weber. ADAR and DDX54 promote genomic stability in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 842.
Macrophage‐derived MLKL in alcohol‐associated liver disease: Regulation of phagocytosis
Authors: Xiaoqin Wu, Xiude Fan, Megan R. McMullen, Tatsunori Miyata, Adam Kim, Vai Pathak, Jianguo Wu, Le Z. Day, Josiah E. Hardesty, Nicole Welch, Jaividhya Dasarathy, Daniela S. Allende, Arthur J. McCullough, Jon M. Jacobs, Daniel M. Rotroff, Srinivasan Dasarathy, Laura E. Nagy
Journal: Hepatology (2022)

Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3)-/- mice are completely protected from ethanol-induced liver injury, Mlkl-/- mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury.
Abstract 1020: Cancer health awareness through screening and education (CHANGE): Understanding community experience accessing cancer care
Authors: Marlo M. Vernon, Samantha Jones, Justin X. Moore, Steve S. Coughlin, Vahe Heboyan, Shakirah Clarke, Barbara Idun, Martha S. Tingen
Journal: Cancer Research (2022)

Abstract INTRODUCTION. Incidence and mortality rates for breast, prostate, and colorectal cancers all exceed national rates in Georgia and are higher among African Americans (AAs). Ensuring culturally competent and equitable health care delivery relies on creating an educated and engaged health care team. Patient stories are powerful examples of community-learned experiences and can be used to educate better providers and health care students who serve diverse populations, particularly when communicating risk and prevention of cancer. The goal of the CHANGE project is to provide a sustainable model of evidence-based cancer awareness through education - with an emphasis on prevention and early detection behaviors. We will develop a health disparities and culturally competent cancer care e-Learning curriculum for health care professionals, hematology-oncology fellows, residents, and medical students at the Medical College of Georgia. METHODS. Thirty community members and stakeholders (93% AA, 76% female, all adults) were recruited through public housing, healthcare clinics and providers, and community organizations. Vignettes describing patient access and care interactions were used in semi-structured interviews to guide conversations about experiences accessing care, attitudes towards cancer prevention, and community cancer beliefs. Interviews were recorded, professionally transcribed, and content analyzed using NVivo 12.0 by two independent raters. RESULTS. Three common themes emerged: accessibility of healthcare (transportation, finances, and difficulties in scheduling were primary barriers); cancer myths and cultural norms (no interpersonal discussion of cancer, seen as “taboo,” cancer will spread if cut into and cancer is contagious); and experience of racial bias in health care (historical racial bias and systemic racism; receipt of treatment and care perceived to be different due to race; lack of AA providers). CONCLUSION. This sample adequately represented those most at risk for cancer in Augusta, GA area. Their shared experiences will be used to design and inform an e-learning curriculum, in conjunction with education on health disparities across the state and specific to the local community. This will provide a comprehensive approach to provider education that will begin to improve patient care satisfaction and health outcomes. Citation Format: Marlo M. Vernon, Samantha Jones, Justin X. Moore, Steve S. Coughlin, Vahe Heboyan, Shakirah Clarke, Barbara Idun, Martha S. Tingen. Cancer health awareness through screening and education (CHANGE): Understanding community experience accessing cancer care [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1020.
Heavy Chain Constant Region Usage in Antibodies to Peptidylarginine Deiminase 4 as a Marker of Disease Subsets in Rheumatoid Arthritis
Authors: E. Gómez‐Bañuelos, J. Shi, H. Wang, M. I. Danila, S. L. Bridges, J. T. Giles, G. P. Sims, F. Andrade, E. Darrah
Journal: Arthritis & Rheumatology (2022)

The study of autoantibody isotypes in autoimmune diseases is useful for identifying clinically relevant endotypes. This study was undertaken to study the prevalence and clinical significance of different isotypes and IgG subclasses of anti-peptidylarginine deiminase 4 (anti-PAD4) autoantibodies in individuals with rheumatoid arthritis (RA).In 196 RA subjects and 64 healthy controls, anti-PAD4 antibody types were determined using enzyme-linked immunosorbent assay. We investigated associations between anti-PAD4 antibodies and clinical outcomes, and relevant features were confirmed in an independent RA cohort.Anti-PAD4 IgG1, anti-PAD4 IgG2, anti-PAD4 IgG3, anti-PAD4 IgG4, anti-PAD4 IgA, and anti-PAD4 IgE antibodies were more frequent in RA patients than healthy controls (P < 0.001). Anti-PAD4 IgG1, anti-PAD4 IgG3, and anti-PAD4 IgE were associated with distinct clinical features. Anti-PAD4 IgG1 was predictive of progressive radiographic joint damage (odds ratio [OR] 4.88, P = 0.005), especially in RA patients without baseline joint damage (40% versus 0%, P = 0.003) or in those negative for anti-cyclic citrullinated peptide and/or rheumatoid factor (OR 32; P = 0.009). IgG1 was also associated with higher levels of C-reactive protein (P = 0.006) and interleukin-6 (P = 0.021). RA patients with anti-PAD4 IgG3 had higher baseline joint damage scores (median Sharp/van der Heijde score 13 versus 7, P = 0.046), while those with anti-PAD4 IgE had higher Disease Activity Score in 28 joints (median 4.0 versus 3.5, P = 0.025), more frequent rheumatoid nodules (31% versus 16%, P = 0.025), and more frequent interstitial lung disease (ground-glass opacification) (24% versus 9%, P = 0.014). Anti-PAD4 IgG1 antibody associations with joint damage were corroborated in an independent RA cohort.Anti-PAD4 IgG1, anti-PAD4 IgG3, and anti-PAD4 IgE antibodies identify discrete disease subsets in RA, suggesting that heavy chain usage drives distinct effector mechanisms of anti-PAD4 antibodies in RA.
Abstract 2959: Investigating the oncogenic effects and mechanisms of the SMYD3 methyltransferase in HPV-negative head and neck squamous cell carcinoma
Authors: Madhavi Murali, Daniel Tsai, Nupur Nigam, Kyunghee Burkitt, Sohyoung Kim, Hui Cheng, Vassiliki Saloura
Journal: Cancer Research (2022)

Abstract Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world and is associated with an overall poor prognosis. The protein methyltransferase SET and MYND domain-containing 3 (SMYD3), which trimethylates H3K4 and H4K20, can stimulate gene transcription and activate several oncogenic pathways, including epithelial-mesenchymal transition, and cell cycle related pathways. Additionally, its expression is associated with a poor prognosis in various cancer types, such as colon and ovarian cancer. This study aims to decipher whether SMYD3 has direct oncogenic effects and relevant mechanisms in HPV-negative HNSCC. Our preliminary results have demonstrated that SMYD3 is significantly overexpressed in HPV-negative HNSCC compared to normal and dysplastic epithelium. SMYD3 knockdown decreased cellular proliferation and clonal capacity in CFAs after siRNA-mediated SMYD3 knockdown in several HPV-negative HNSCC cell lines or CRISPR-mediated SMYD3 knockout. Cell cycle analysis of CRISPR SMYD3 KO cell lines showed a significant decrease in the S phase, supporting that cell cycle arrest may be a mechanism through which this decreased cellular proliferation occurs. Nuclear/cytoplasmic dissociation and western blotting of 6 HPV-negative HNSCC cell lines, and immunohistochemistry for SMYD3 in primary and recurrent/metastatic HPV-negative HNSCC tumor tissues have identified the expression of SMYD3 in both the cytoplasm and nucleus, with greater expression in the cytoplasm than the nucleus. Ongoing experiments aim to investigate the effects of SMYD3 knockdown on the global proteome, as well as its effects on histone post-translational modifications in HPV-negative HNSCC cell lines. Genome-wide mapping for SMYD3, H3K4me3 and H4K20me3 in HPV- negative HNSCC cells using CUT&amp;RUN assays are ongoing with the goal to identify direct downstream gene targets regulated by human SMYD3. Finally, we plan to investigate if SMYD3 knockout decreases tumor growth in NSG xenografts. This study may provide the biological rational to target SMYD3 as a novel therapeutic avenue in HPV-negative HNSCC. Citation Format: Madhavi Murali, Daniel Tsai, Nupur Nigam, Kyunghee Burkitt, Sohyoung Kim, Hui Cheng, Vassiliki Saloura. Investigating the oncogenic effects and mechanisms of the SMYD3 methyltransferase in HPV-negative head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2959.
Abstract 2731: Longitudinally modeling anti-neoantigen immunity under paradigms of immunodominance
Authors: Tim Qi, Benjamin Vincent, Yanguang Cao
Journal: Cancer Research (2022)

Abstract Neoantigen clonal architecture is known to influence the efficacy of immunotherapy. The immunodominance of clonal neoantigens over a canvas of heterogeneous subclonal neoantigens is particularly challenging to recapitulate in experimental models. We developed a computational model of neoantigen evolution that longitudinally tracks the “presentome” - that is, a cell’s aggregate neoantigen repertoire and HLA status - of simulated non-small cell lung cancer (NSCLC) prior to and during treatment with checkpoint blockade. Using neoantigen immunogenicity parameters from published reports, we first recapitulated the presentome of early-stage NSCLC. Upon simulating checkpoint blockade treatment of advanced NSCLC, we found salient correlates and consequences of response, including a profound clonal collapse among completely responding tumors. Our work could be adapted to longitudinally model the neoantigen architecture of other cancers and modalities of immunotherapy, ultimately informing cognizant strategies for future therapeutic development. Citation Format: Tim Qi, Benjamin Vincent, Yanguang Cao. Longitudinally modeling anti-neoantigen immunity under paradigms of immunodominance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2731.
Abstract 5007: Discovery of stromal targets in pancreatic cancer
Authors: Shengjun Li, Jeong-Bin Park, Hyung-Jun Im
Journal: Cancer Research (2022)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited treatment options. Development of stroma targeting therapeutics for PDAC is gaining attention because PDAC has a unique tumor microenvironment with dense tumor stroma and the tumor stroma is a critical mediator of PDAC progression. Herein, we discovered pancreatic cancer stroma-specific cell surface markers by integrative analysis of single cell RNA sequencing and cell surface marker database. Methods: Single cell RNA sequencing data of PDAC tissue (n = 3, GSE154778) and normal pancreas tissue (n = 3, GSE131886) was obtained from Gene Expression Omnibus database. Using Seurat package, the data from each sample integrated and the cells were clustered. We selected stroma cell cluster for differential analysis to obtain the genes enriched in PDAC stroma. Then, the intersection of the PDAC stroma specific genes with the gene set of SurfaceomeDB was obtained, which allowed us to obtain the stroma cell surface markers that are highly expressed in PDAC. The marker genes were validated in 1) 36 pairs of PDAC and normal tissue samples from a RNA sequencing data (GSE15471), and 2) 143 PDAC samples in The Cancer Genome Atlas (TCGA), 328 normal pancreatic tissues in Genotype-Tissue Expression (GTEx) database (https://www.gtexportal.org). Results: The cells from PDAC and normal pancreas were clustered into ductal/tumor, stromal and immune cell clusters according to the expression of cell-type specific marker genes. We identified variably expressed genes between PDAC and normal cells within the stromal cell cluster. Among the PDAC stroma-specific genes, we could obtain 360 cell surface markers using SurfaceomeDB. The top ten PDAC stroma-specific cell surface marker genes were MXRA8, ANTXR1, THY1, SCD1, LY6E, BST2, GPNMB, CDH11, GJB2, and CD55. To validate the results, we compared the expression levels of the top 10 genes between pancreatic cancer tissue and adjacent normal pancreatic tissue. We found that the expression levels of the genes were significantly higher in the cancer tissue compared to the normal pancreatic tissue. We also confirmed that the expression levels of 10 genes were significantly higher in all stages of PDAC compared to normal tissues in a combined RNA sequencing dataset from healthy human pancreatic tissue from GTEx and pancreatic cancer patients from TCGA. Conclusion: We identified pancreatic cancer stroma-specific cell surface markers using single-cell RNA sequencing data and SurfaceomeDB. The markers can be utilized in development of various pancreatic cancer stroma targeted therapeutics including antibodies, antibody-drug conjugates, peptides, cell therapeutic and nanoparticles. Citation Format: Shengjun Li, Jeong-Bin Park, Hyung-Jun Im. Discovery of stromal targets in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5007.